Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses

ABSTRACT

The invention concerns compounds of general formula (I) wherein: R1, R2, R3, R4, R5 and R6 are as defined in claim 1. Said compounds are useful in the treatment of pathologies related to the insulin-resistance syndrome.

[0001] The present invention relates to amine-containing derivatives ofdihydro-1,3,5-triazine which are useful in the treatment of pathologicalconditions associated with the insulin-resistance syndrome.

[0002] Amine-containing derivatives of dihydro-1,3,5-triazine havinghypoglycaemic properties have been described in JP-A-73 64 088 andJP-A-79 14 986.

[0003] The aim of the present invention is to provide novel compoundshaving improved properties.

[0004] The subject of the present invention is thus a compound ofgeneral formula (I):

[0005] in which:

[0006] R1, R2, R3 and R4 are chosen independently from the groups:

[0007] H,

[0008] (C1-C20)alkyl substituted or otherwise with halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C3-C8)cycloalkyl,

[0009] (C2-C20)alkylene substituted or otherwise with halogen,(C1-C5)alkyl, (C1-C5)alkoxy,

[0010] (C2-C20)alkyne substituted or otherwise with halogen,(C1-C5)alkyl, (C1-C5)alkoxy,

[0011] (C3-C8)cycloalkyl substituted or otherwise with (C1-C5)alkyl,(C1-C5)alkoxy,

[0012] (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosenfrom N, O, S and substituted or otherwise with (C1-C5)alkyl,(C1-C5)alkoxy,

[0013] (C6-C14)aryl(C1-C20)alkyl substituted or otherwise with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0014] (C6-C14)aryl substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl (C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0015] (C1-C13)heteroaryl carrying one or more heteroatoms chosen fromN, O, S and substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0016] it being possible for R1 and R2, on the one hand, and R3 and R4,on the other hand, to form with the nitrogen atom an n-membered ring (nbetween 3 and 8) comprising or otherwise one or more heteroatoms chosenfrom N, O, S and being capable of being substituted with one or more ofthe following groups: amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl (C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl,

[0017] R5 and R6 are chosen independently from the groups:

[0018] H,

[0019] (C1-C20)alkyl substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5) alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0020] (C2-C20)alkylene substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0021] (C2-C20)alkyne substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0022] (C3-C8)cycloalkyl substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0023] (C3-C8)heterocycloalkyl carrying one or more heteroatoms chosenfrom N, O, S and substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0024] (C6-C14)aryl substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0025] (C1-C13)heteroaryl carrying one or more heteroatoms chosen fromN, O, S and substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0026] (C6-C14)aryl(C1-C5)alkyl substituted or otherwise with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0027] it being possible for R5 and R6 to form with the carbon atom towhich they are attached an m-membered ring (m between 3 and 8)comprising or otherwise one or more heteroatoms chosen from N, O, S andbeing capable of being substituted with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl,

[0028] or being capable of forming with the carbon atom a C10-C30polycyclic residue substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

[0029] it being possible for the nitrogen atom of a hetero-cycloalkyl orheteroaryl group to be substituted with a (C1-C5)alkyl,(C3-C8)cycloalkyl, (C6-C14)aryl, (C6-C14)aryl(C1-C5)alkyl or (C1-C6)acylgroup, with the exclusion of the compounds of formula I in which:

[0030] a—R1=H, R2=H, R3=H, R5=CH3, R6=CH3 and R4=phenethyl,phenoxyethyl, 2-phenylthioisopropyl or benzyl;

[0031] b—R1=H, R2=H, R3=H or CH3, R4=H, methyl, butyl or phenethyl, R5=Hor ethyl and R6 is 3-methyl-5-isoxazolyl, 5-methyl-3-isoxazolyl,3-methyl-5-pyrazolyl or (5-methyl-3-isoxazolyl)methyl,

[0032] c—R1, R2, R3 and R4 represent a hydrogen atom,

[0033] as well as the tautomeric, enantiomeric, diastereoisomeric andepimeric forms and the pharmaceutically acceptable salts.

[0034] The expression m-membered ring formed by R5 and R6 is understoodto mean in particular a saturated ring such as a cyclohexyl, piperidinylor tetrahydropyranyl group.

[0035] The expression polycyclic group formed by R5 and R6 is understoodto mean an optionally substituted carbon-containing polycyclic group andin particular a steroid residue.

[0036] A particular group of compounds of formula (I) is that in whichR5 is hydrogen.

[0037] Another particular group of compounds of formula (I) is that inwhich R5 and R6 form with the carbon atom to which they are attached anm-membered ring (m between 3 and 8) comprising or otherwise one or moreheteroatoms chosen from N, O, S and being capable of being substitutedwith one or more of the following groups: (C1-C5)alkyl, amino, hydroxyl,(C1-C5)alkylamino, (C1-C5)alkoxy, (C1-C5)alkylthio, (C6-C14)aryl,(C6-C14)aryl(C1-C5)alkoxy,

[0038] or form with the carbon atom a C10-C30 polycyclic residuesubstituted or otherwise with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl.

[0039] Another particular group of compounds of formula (I) is that inwhich R5 and R6 are chosen independently from the groups:

[0040] (C1-C20)alkyl substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.

[0041] A more particular group of compounds of formula (I) is that inwhich R1 and R2 are chosen independently from the groups specified abovewith the exception of the hydrogen atom and R3 and R4 represent ahydrogen. More particularly, a preferred group of compounds of formula(I) is that in which R1 and R2 are an alkyl, advantageously methyl,group and R3 and R4 represent a hydrogen.

[0042] The invention also relates to the tautomeric, enantiomeric,diastereoisomeric and epimeric forms of the compounds of general formula(I).

[0043] The compounds of general formula (I) possess basic nitrogen atomswhich may be monosalified or disalified with organic or inorganic acids.

[0044] The compounds of general formula (I) may be prepared by reactinga compound of general formula (II)

[0045] in which R1, R2, R3 and R4 are as defined above, with a compoundof general formula (III), (IV) or (V)

[0046] in which R5 and R6 are as defined above and R7 is a methyl orethyl group, in a polar solvent (for example ethanol ordimethylformamide) in the presence of an organic acid (for examplecamphorsulphonic acid) or of an inorganic acid (for example hydrochloricacid).

[0047] The compounds of general formula (II) are biguanides whosesynthesis is routine to every person skilled in the art. We will citefor example some publications describing the synthesis of such compounds(FR 1537604, FR 2132396; K. H. Slotta and R. Tschesche, Ber., 1929(62b), 1398; S. L. Shapiro, V. A. Parrino, E. Rogow and L. Freedman, J.Org. Chem., 1959 (81), 3725; S. L. Shapiro, V. A. Parrino and L.Freedman, J. Org. Chem., 1959 (81), 3728; S. L. Shapiro, V. A. Parrinoand L. Freedman, J. Org. Chem., 1959 (81), 4636).

[0048] The compounds according to the present invention are useful inthe treatment of pathological conditions associated with theinsulin-resistance syndrome (X syndrome).

[0049] Insulin-resistance is characterized by a reduction in the actionof insulin (cf. Presse Médicale, 1997, 26 (No. 14), 671-677) and isinvolved in a large number of pathological states, such as diabetes andmore particularly non-insulin-dependent diabetes (type II diabetes orNIDDM), dyslatupidaemia, obesity, high blood pressure, as well ascertain microvascular and macrovascular complications such asatherosclerosis, retinopathies and neuropathies.

[0050] In this regard, reference may be made for example to Diabetes,vol. 37, 1988, 1595-1607; Journal of Diabetes and its complications,1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32.

[0051] In particular, the compounds of the invention have a highhypoglycaemic activity.

[0052] The compounds according to the present invention can also be usedto treat chronic complications which are in particular due to theformation of “advanced glycosylation end-products” noted AGEs which arederived from the glycoxidation reaction between glucose, its oxidationderivatives and the amino functional groups of proteins, including theso-called Maillard reactions for glycation of glyoxal for example.

[0053] Indeed, recently published data clearly show the impact of AGEson renal complications (Nephr. Dial. Transplant., 2000, 15 (suppl 2),7-11), on atherosclerosis, Alzheimer's disease and otherneurodegenerative diseases (Glycoconj. J., 1998, 15 (10), 1039-42; BrainRes., 2001, 888(2), 256). The formation of AGE may also play animportant part in the pathogenesis of angiopathy, in particular indiabetics, and also in senility (J. Neuropathol. Exp. Neurol., 2000, 59(12), 1094).

[0054] The subject of the present invention is therefore alsopharmaceutical compositions comprising, as active ingredient, a compoundaccording to the invention.

[0055] These pharmaceutical compositons are particularly intended fortreating diabetes, pathological conditions due to the formation of AGEs,such as, in particular, renal complications, atherosclerosis,angiopathy, Alzheimer's disease, neurodegenerative diseases andsenility.

[0056] The pharmaceutical compounds according to the invention may beprovided in forms intended for administration by the parenteral, oral,rectal, permucosal or percutaneous route.

[0057] They will therefore be provided in the form of injectablesolutions or suspensions or multidose vials, in the form of uncoated orcoated tablets, sugar-coated tablets, capsules, gelatin capsules, pills,cachets, powders, suppositories or rectal capsules, solutions orsuspensions, for percutaneous use in a polar solvent, for permucosaluse.

[0058] The excipients which are suitable for such administrations arethe derivatives of cellulose or of microcrystalline cellulose, thealkaline-earth carbonates, magnesium phosphate, starches, modifiedstarches, lactose for the solid forms.

[0059] For rectal use, cocoa butter or the stearates of polyethyleneglycol are the preferred excipients.

[0060] For parenteral use, water, aqueous solutions, physiologicalsaline, isotonic solutions are the vehicles most conveniently used.

[0061] The dosage may vary within wide limits (0.5 mg to 1 000 mg)according to the therapeutic indication and the route of administration,as well as the age and weight of the subject.

[0062] By way of example, here are a few biguanides of formula II usedin the synthesis of derivatives of formula I. TABLE I m.p. in FormulaSalt ° C. (Köfler) A

HCl 223-225 B

HCl 176-178 C

HCl 230-232 D

HCl 210-212 E

HCl 254-256 F

HCl 158-160 G

HCl 100-102

[0063] The following examples illustrate the preparation of thecompounds of formula I.

EXAMPLE 1

[0064] Synthesis of2-amino-3,6-dihydro-4-dimethylamino-6-ethyl-1,3,5-triazine hydrochloride

[0065] 23 ml of propionaldehyde and 3.6 g of camphorsulphonic acid areadded to a solution of compound A (25.7 g; 0.155 mol) in 200 ml of DMF.After refluxing for 2 hours, the solvent is removed under vacuum and 100ml of acetonitrile are added. The solid formed is drained and dried(21.9 g; 69%). m.p. =218-220° C.

[0066]¹H NMR (DMSO-d6, 200 MHz): 1.10 (t, 3H); 1.80 (m, 2H) 3.20 (s,6H); 4.83 (m, 1H); 7.57 (m, 2H); 8.65 (s, 1H); 8.90 (s, 1H)

[0067]¹³C NMR (DMSO-d6, 50 MHz): 6.41 (CH3); 27.59 (CH2); 35.64 (CH3);60.75 (CH); 155.01 (C═N); 156.67 (C═N)

EXAMPLE 2

[0068] Synthesis of2,4-bisdimethylamino-3,6-dihydro-6-methyl-1,3,5-triazine hydrochloride

[0069] 61 ml of acetal and 5 g of camphorsulphonic acid are added to asolution of compound E (41.10 g; 0.212 mol) in 200 ml of absoluteethanol. The whole is heated under reflux for 72 hours and thenconcentrated. The crude material is triturated with acetonitrile and thesolid formed is drained and then recrystallized from acetonitrile. 24 g(51.5%) of a solid are obtained.

[0070] m.p. =200-202° C.

[0071]¹H NMR (DMSO-d6, 200 MHz): 1.34 (d, 3H); 3.02 (s, 6H) 4.72 (m,1H); 4.83 (m, 1H); 8.80 (s, 2H)

[0072]¹³C NMR (DMSO-d6, 50 MHz): 22.59 (CH3); 37.76 (CH3); 59.02 (CH);156.35 (C═N)

[0073] The characteristics of these compounds and of other compounds offormula I are given in Table II below: TABLE II m.p. in ° C. ¹³C NMRFormula Salt (Köfler) 50.32 MHz 1

HCl 218-220 DMSO-d6 6.41, CH3 27.59, CH2 35.64, 2 CH3 60.75, CH 155.01,156.67, 2 quaternary C 2

HCl 200-202 DMSO-d6 22.58, 37.75, 5 CH3 59.01, CH 156.34, 2 quaternary C3

193-195 DMSO-d6 32.06, 37.40, 2 CH3 67.85, 158.16, 3 quaternary C 4

HCl 243-245 DMSO-d6 21.66, 25.19, 37.72, 3 CH2 37.89, 2 CH3 67.51,156.83, 158.24, 3 quaternary C 5

Methane- sulphonate 174-176 DMSO-d6 34.31, 41.36, 44.79, 5 CH3 69.75,160.30, 161.44, 3 quaternary C 6

138-140 DMSO-d6 28.04, CH2 30.84, 37.40, 3 CH3 42.06, 62.24, 2 CH270.00, 158.24, 158.69, 3 quaternary C 7

HCl 150-152 DMSO-d6 27.39, CH2 28.78, 39.14, 3 CH3 40.21, 61.30, 2 CH268.46, 156.48, 157.84 3 quaternary C 8

HCl 124-126 DMSO 28.95, 38.65, 2 CH3 42.77, CH2 69.75, quaternary C115.93, CH2 149.12, CH 155.70, 156.16, 2 quaternary C 9

HCl 149-151 DMSO-d6 26.20, 32.39, 40.73, 6 CH3 46.16, CH 60.09, 158.83,159.14, 3 quaternary C 10

HCl 239-241 DMSO-d6 37.78, 2 CH3 62.39, CH 126.66, 129.47, 5 CH 141.87,156.52, 158.38, 3 quaternary C 11

HCl 221-223 DMSO-d6 37.23, 55.60, 3 CH3 61.88, CH 114.32, 127.66, 4 CH133.17, 156.11, 157.86, 159.93, 4 quaternary C 12

HCl 251-253 DMSO-d6 37.75, 2 CH3 62.67, 116.16, 128.16, 5 CH 131.72,156.64, 158.31, 158.88, 4 quaternary C 13

>260 DMSO-d6 39.55, 39.71, 2 CH3 65.92, 117.71, 130.17, 5 CH 131.72,156.64, 158.31, 158.88, 4 quaternary C 14

Fumarate 172-174 15.48, 29.33, 3 CH3 35.68, CH2 37.43, 2 CH3 65.71,quaternary C 135.47, 2 CH 156.21, 156.63, 168.35, 4 quaternary C 15

HCl 250-252 DMSO-d6 28.74, 37.38, 6 CH3 66.53, 155.28, 3 quaternary C 16

HCl 183-185 DMSO-d6 32.62, 40.96, 5 CH3 69.37, 159.30, 160.19, 3quaternary C 17

HCl >260 DMSO-d6 22.78, 2 CH3 28.96, 2 CH2 40.13, 2 CH3 42.73, 2 CH265.63, 155.42, 155.71, 3 quaternary C 18

HCl 229-231 DMSO-d6 22.97, 37.76, 3 CH3 58.59, CH 157.85, 159.39, 2quaternary C 19

HCl >260 Concise spectrum DMSO-d6 69.06, 159.78, 161.17, 3 quaternary C20

carbonate 170-180 CF3CO2D 22.43, 25.71, 36.86, 38.71, 43.12, 7 CH267.88, quaternary C 127.47, 129.55, 129.93, 5 CH 140.22, 158.72, 159.65,3 quaternary C 21

Carbonate >140 DMSO-d6 20.51, CH3 24.73, 25.39, 2 CH2 39.98, 2 CH346.44, 47.91, 2 CH2 58.49, CH 154.58, 156.63, 160.61, 3 quaternary C 22

HCl >260 DMSO-d6 21.18, 24.68, 3 CH2 27.26, CH3 37.00, 2 CH2 37.37, 2CH3 67.12, 155.89, 156.86, 3 quaternary C 23

HCl 248-250 DMSO-d6 15.11, CH3 21.17, 24.70, 35.39, 37.04, 6 CH2 37.36,2 CH3 67.09, 155.90, 156.21, 3 quaternary C 24

HCl >260 Concise spectrum DMSO-d6 67.46, 68.80, 156.76, 157.47, 157.99,159.14, 3 quaternary C 175.90, 176.11, COOH 25

HCl >260 Concise spectrum DMSO-d6 64.87, 69.85, 2 CHOH 66.55, 154.91,156.19, 3 quaternary C 173.75, COOH 26

HCl 91—93 DMSO-d6 25.76, 37.28, 3 CH3 43.28, CH2 64.27, CH 115.21, CH2137.55, CH 159.79, 160.77, 2 quaternary C 27

HCl >260 DMSO-d6 25.69, 27.25, 4 CH2 39.13, 2 CH3 67.25, quaternary C70.01, CH2 72.50, CH 128.17, 128.34, 129.07, 5 CH 139.79, 156.81,158.30, 3 quaternary C 28

HCl >250 DMSO-d6 29.83, 34.4, 4 CH2 38.83, 2 CH3 66.17, CH 67.06,156.25, 157.28, 3 quaternary C 29

Carbonate 133-135 DMSO-d6 7.25, 26.81, 2 CH3 34.32, CH2 37.17, 2 CH368.59, 156.46, 157.71, 160.78, 4 quaternary C 30

Carbonate 140-144 8.68, 2 CH3 34.54, 2 CH2 37.91, 2 CH3 74.98, 157.84,159.14, 160.82, 4 quaternary C 31

HCl 207-209 DMSO-d6 22.50, 2 CH2 38.00, 2 CH3 39.78, 2 CH2 75.51,157.18, 158.37, 3 quaternary C 32

Carbonate decomposes DMSO-d6 14.55, CH3 17.20, CH2 37.45, 2 CH3 39.00,CH2 62.43, CH 157.52, 159.04, 160.65, 3 quaternary C 33

HCl >260 D2O 37.90, 2 CH3 48.69, CH2 154.82, 156.33, 2 quaternary C 34

Para- toluene- sulphonate 201-203 DMSO-d6 21.65, CH3 25.95, 26.07,26.58, 26.89, 27.50, 5 CH2 37.56, 2 CH3 44.74, 66.56, 126.32, 129.08, 6CH 138.99, 145.86, 158.18, 156.86, 4 quaternary C 35

HCl 157-159 DMSO-d6 29.10, 37.86, 4 CH3 65.90, 154.82, 156.33, 3quaternary C 36

Para- toluene- sulphonate 251-253 DMSO-d6 21.14, 37.26, 3 CH3 114.80,120.70, 126.41, 132.12, CF3 125.82, 128.54, 4 CH 138.37, 145.49, 155.78,157.18, 4 quaternary C 37

Para- toluene- sulphonate 159-161 DMSO-d6 21.17, 36.95, 3 CH3 42.60, CH262.10, 126.86, 127.21, 128.55, 128.63, 130.32, 10 CH 135.14, 138.30,145.67, 156.18, 157.44, 5 quaternary C 38

HCl >260 DMSO-d6 37.41, 2 CH3 37.47, 62.73, 4 CH2 64.76, 156.35, 157.77,3 quaternary C 39

HCl >260 DMSO-d6 34.12, 2 CH2 38.63, 42.60, 3 CH3 48.72, 2 CH2 64.01,156.11, 157.78, 3 quaternary C 40

HCl 225-227 DMSO-d6 37.19, 2 CH3 56.58, 107.94, 110.93, 144.00, 4 CH152.78, 155.85, 157.47, 3 quaternary C 41

Para- toluene- sulphonate 194-196 DMSO-d6 21.17, 37.03, 3 CH3 60.37, CH70.05, CH2 115.08, 121.60, 125.84, 128.54, 129.95, 10 CH 138.28, 145.64,156.40, 157.70, 158.45, 5 quaternary C 42

HCl >260 DMSO-d6 24.12, 37.15, 5 CH3 39.90, quaternary C 68.39, CH156.57, 158.10, 2 quaternary C 43

HCl decomposes DMSO-d6 22.95, 23.05, 2 CH3 25.87, CH 36.94, 2 CH3 45.71,CH2 62.38, CH 157.15, 157.42, 158.34, 3 quaternary C 44

HCl 213-215 DMSO-d6 15.99, 17.12, 2 CH3 34.57, CH 37.17, 2 CH3 65.68, CH156.45, 158.12, 2 quaternary C 45

Para- toluene- sulphonate 217-219 DMSO-d6 21.17, CH3 22.53, 24.48,25.30, 3 CH2 37.20, 2 CH3 40.07, 64.37, 2 CH 125.68, 125.83, 127.19,128.61, 6 CH 138.53, 145.24, 156.06, 157.36, 4 quaternary C

[0074] Results of pharmacological studies will be given below.

[0075] Study of the Antidiabetic Activity in the Nostz Rat

[0076] The antidiabetic activity of the compounds of formula (I)administered orally was determined on an experimental model ofnon-insulin-dependent diabetes induced in rats by Streptozotocin.

[0077] The non-insulin-dependent diabetes model is obtained in rats byneonatal injection (on the day of birth) of streptozotocin.

[0078] The diabetic rats used were 8 weeks old. The animals were kept,from the day of their birth to the day of the experiment, in an animalhouse at a controlled temperature of 21 to 22° C. and subjected to afixed cycle of light (from 7 am to 7 pm) and darkness (from 7 pm to 7am). Their diet consisted of a maintenance diet, water and food wereprovided “ab libitum”, with the exception of the 2 hours of fastingpreceding the tests when the food is withdrawn (postabsorptive state).

[0079] The rats were treated by the oral route for one (D1) or four (D4)days with the product to be tested. Two hours after the lastadministration of the product and 30 minutes after anaesthetizing theanimals with sodium pentobarbital (Nembutal®), 300 μl of blood sampleare collected from the end of the tail.

[0080] By way of example, results obtained are assembled in Table III.These results show the efficacy of the compounds of formula (I) inreducing glycaemia in the diabetic animals. These results are expressedas a percentage variation of glycaemia at D1 and D4 (number of days oftreatment) relative to D0 (before the treatment). TABLE III 20 mg/kg/D200 mg/kg/D Compounds D1 D4 D1 D4  1 −7 −2 −13 −15  2 −11 −10 −12 −12  3−10 −8 −18 −22  4 0 −1 −20 −10  7 −8 −11 −10 −16 15 −8 −9 −4 −5 17 −12−8 −8 −14 18 −6 −4 −29 −28 19 −10 −6 −4 −14 21 −7 −2 −21 −24 22 −23 −16−13 0 25 −4 −11 −7 −6 26 −6 −11 −14 −9 27 −14 −9 −12 −13 28 −4 −1 −4 −1331 −5 −11 −3 −15 32 2 0 −22 −18 33 −7 −6 −9 −14 34 −5 −15 −6 −21 37 −7−8 −10 −15 39 −6 −6 −4 −7 40 −8 −12 −18 −18 42 −5 −4 −26 −17 43 −4 −16−12 −17 44 −7 −6 −22 −25

[0081] Study of the Antiglycation Activity

[0082] The compounds (1) are also capable of inhibiting the so-calledMaillard reactions by “capturing effect” on the α-dicarbonyl-containingderivatives such as glyoxal—this is the antiglycation effect. ThisMaillard reaction inhibiting effect of the compounds according to theinvention was studied in vitro by assaying ketamines (“fructosamines”)produced during the incubation of albumin with methylglyoxal in thepresence or otherwise of a compound of formula (I) according to theinvention.

[0083] A solution of bovine albumin at 6.6 mg/ml in 0.2 M phosphatebuffer, pH 7.4, is incubated with 1 mM methylglyoxal in the presence orotherwise of a compound according to the invention at a concentration of10 mM. The incubation is carried out under sterile conditions at 37° C.for 6 days. At the end of the incubation period, the quantity ofketamines is measured with a commercially available fructosamine assaykit (“FRA” kit, product reference: 0757055, Roche S. A. products)according to the manufacturer's instructions.

[0084] By way of example, results obtained under these experimentalconditions are assembled in Table IV: level of fructosamine afterincubation of the albumin with the methylglyoxal in the presence ofcompounds (I) according to the invention in relation to the level offructosamine when albumin is incubated with methylglyoxal in the absenceof the compounds (I) according to the invention. TABLE IV Reduction inthe level of Compounds (I) fructosamines (%)  1 62 10 80 11 89 12 90 1395 18 69 33 79 34 64 36 66 37 65 40 66 43 68 45 67

1. Compounds of general formula (I):

in which: R1, R2, R3 and R4 are chosen independently from the groups: H,(C1-C20)alkyl substituted or otherwise with halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C3-C8)cycloalkyl, (C2-C20)alkylene substituted orotherwise with halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C2-C20)alkynesubstituted or otherwise with halogen, (Cl-CS)alkyl, (C1-C5)alkoxy,(C3-C8)cycloalkyl substituted or otherwise with (C1-C5)alkyl,(C1-C5)alkoxy, (C3-C8)heterocycloalkyl carrying one or more heteroatomschosen from N, O, S and substituted or otherwise with (C1-C5)alkyl,(C1-C5)alkoxy, (C6-C14)aryl (C1-C20)alkyl substituted or otherwise withamino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl-(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, (C6-C14)aryl substituted or otherwisewith amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, (C1-C13)heteroaryl carrying one or moreheteroatoms chosen from N, O, S and substituted or otherwise with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5) alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, it beingpossible for R1 and R2, on the one hand, and R3 and R4, on the otherhand, to form with the nitrogen atom an n-membered ring (n between 3 and8) comprising or otherwise one or more heteroatoms chosen from N, O, Sand being capable of being substituted with one or more of the followinggroups: amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, R5 and R6 are chosen independently fromthe groups: H, (C1-C20)alkyl substituted or otherwise with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,(C2-C20)alkylene substituted or otherwise with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, (C2-C20)alkynesubstituted or otherwise with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl, (C3-C8)cycloalkyl substitutedor otherwise with amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl, (C3-C8)heterocycloalkyl carrying one ormore heteroatoms chosen from N, O, S and substituted or otherwise withamino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl orcarboxyethyl, (C6-C14)aryl substituted or otherwise with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,(C1-C13)heteroaryl carrying one or more heteroatoms chosen from N, O, Sand substituted or otherwise with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14) aryloxy, (C6-C14)aryl-(C1-C5) alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl, (C6-C14)aryl(C1-C5)alkylsubstituted or otherwise with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl-(C1-C5) alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl, it being possible for R5 and R6to form with the carbon atom to which they are attached an m-memberedring (m between 3 and 8) comprising or otherwise one or more heteroatomschosen from N, O, S and being capable of being substituted with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, or beingcapable of forming with the carbon atom a C10-C30 polycyclic residuesubstituted or otherwise with amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl, it being possible for thenitrogen atom of a hetero-cycloalkyl or heteroaryl group to besubstituted with a (C1-C5)alkyl, (C3-C8)cycloalkyl, (C6-C14)aryl,(C6-C14)aryl(C1-C5)alkyl or (C1-C6)acyl group, with the exclusion of thecompounds of formula I in which: a—R1=H, R2=H, R3=H, R5=CH3, R6=CH3 andR4=phenethyl, phenoxyethyl, 2-phenylthioisopropyl or benzyl; b—R1=H,R2=H, R3=H or CH3, R4=H, methyl, butyl or phenethyl, R5=H or ethyl andR6 is 3-methyl-5-isoxazolyl, 5-methyl-3-isoxazolyl, 3-methyl-5-pyrazolylor (5-methyl-3-isoxazolyl)methyl, c—R1, R2, R3 and R4 represent ahydrogen atom, as well as the tautomeric, enantiomeric,diastereoisomeric and epimeric forms and the pharmaceutically acceptablesalts.
 2. Compounds of formula (I) according to claim 1, in which R5 ishydrogen.
 3. Compounds of formula (I) according to claim 1, in which R5and R6 form with the carbon atom to which they are attached anm-membered ring (m between 3 and 8) comprising or otherwise one or moreheteroatoms chosen from N, O, S and which can be substituted with amino,hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, or form withthe carbon atom a C10-C30 polycyclic residue substituted or otherwisewith amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl orcarboxyethyl.
 4. Compounds of formula (I) according to claim 1, in whichR5 is a (C2-C20)alkyl group substituted with amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.
 5. Compoundsof formula (I) according to claim 1, in which R5 and R6 are chosen from(C1-C20)alkyl groups substituted or otherwise with amino, hydroxyl,thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl-(C1-C5) alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.
 6. Compoundsof formula (I) according to any one of claims 1 to 5 in which R1 and R2are chosen independently from the groups specified in claim 1 with theexception of the hydrogen atom and R3 and R4 represent a hydrogen. 7.Compounds of formula (I) according to claim 6, in which R1 and R2 are amethyl group and R3 and R4 represent a hydrogen.
 8. Method for preparinga compound according to claim 1 comprising reacting a compound ofgeneral formula (II)

in which R1, R2, R3 and R4 are as defined above, with a compound ofgeneral formula (III), (IV) or (V)

in which R5 and R6 are as defined above and R7 is a methyl or ethylgroup, in a polar solvent in the presence of an organic or inorganicacid.
 9. Pharmaceutical composition comprising, as active ingredient, acompound according to any one of claims 1 to
 7. 10. Use of a compoundaccording to any one of claims 1 to 7, for the manufacture of amedicament intended for the treatment of pathological conditionsassociated with the insulin-resistance syndrome.
 11. Use of a compoundaccording to any one of claims 1 to 7, for the manufacture of amedicament intended for the treatment of diabetes.
 12. Use of a compoundaccording to any one of claims 1 to 7, for the manufacture of amedicament intended for the treatment of pathological conditions due tothe formation of AGEs.
 13. Use of a compound according to any one ofclaims 1 to 7, for the manufacture of a medicament intended for thetreatment of pathological conditions selected from renal complications,atherosclerosis, angiopathy, Alzheimer's disease, neurodegenerativediseases and senility.